Phase I Trial of Expanded, Activated Autologous NK-cell Infusions with Trastuzumab in Patients with HER2-positive Cancers
- 1 September 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 26 (17), 4494-4502
- https://doi.org/10.1158/1078-0432.ccr-20-0768
Abstract
Purpose: Natural killer (NK) cells exert antibody-dependent cell cytotoxicity (ADCC). We infused expanded, activated autologous NK cells to potentiate trastuzumab-mediated ADCC in patients with HER2-positive malignancies. Patients and Methods: In a phase I trial, patients with treatment-refractory HER2-positive solid tumors received trastuzumab, with or without bevacizumab, and autologous NK cells expanded by 10-day coculture with K562-mb15-41BBL cells. Primary objectives included safety and recommended phase II dose determination; secondary objectives included monitoring NK-cell activity and RECIST antitumor efficacy. Results: In 60 cultures with cells from 31 subjects, median NK-cell expansion from peripheral blood was 340-fold (range, 91–603). NK cells expressed high levels of CD16, the mediator of ADCC, and exerted powerful killing of trastuzumab-targeted cells. In the 22 subjects enrolled in phase I dose escalation, trastuzumab plus NK cells were well tolerated; MTD was not reached. Phase IB (n = 9) included multiple cycles of NK cells (1 × 107/kg) and addition of bevacizumab. Although no objective response was observed, 6 of 19 subjects who received at least 1 × 107/kg NK cells at cycle 1 had stable disease for ≥6 months (median, 8.8 months; range 6.0–12.0). One patient, the only one with the high-affinity F158V CD16 variant, had a partial response. Peripheral blood NK cells progressively downregulated CD16 postinfusion; paired tumor biopsies showed increased NK cells, lymphocytic infiltrates, and apoptosis posttreatment. Conclusions: NK-cell therapy in combination with trastuzumab was well tolerated, with target engagement and preliminary antitumor activity, supporting continued assessment of this approach in phase II trials.Keywords
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Funding Information
- National Medical Research Council (NMRC/CSA/015/2009, NMRC/CSA-SI/0004/2015, NMRC/CG/012/2013, NMRC/CG/M005/2017_NCIS, NMRC/STaR/0025/2015)
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